Neuropeptides are small biologically active peptides which are widely distributed throughout the body and have functions from neurotransmitter to growth factor. Much evidence has indicated that neuropeptides have anti-inflammatory capabilities. Among the many neuropeptides are melanocortic peptides (melanocortins), which bind to and stimulate melanocortin (MC) receptors. An example of a melanocortin includes α-melanocyte-stimulating hormone (α-MSH), mainly known for its ability to regulate peripheral pigmentation, but is also known to have anti-inflammatory and immunomodulatory capabilities. α-MSH neuropeptide has been detected in several organs and is produced by neurons, pituitary, gut, skin, and immune cells.
The immunomodulatory capabilities of α-MSH have been demonstrated in models of contact hypersensitivity where hapten-specific tolerance was induced by injection with α-MSH and in suppressing bacterial endotoxin-mediated inflammation. Also, α-MSH has been shown to have therapeutic activity in many animal disease models such as inflammatory bowel disease, arthritis, and experimental heart transplantation. Other animal models of brain inflammation, renal injury and liver inflammation have demonstrated anti-inflammatory effects with this neuropeptide. α-MSH suppresses production of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1 and inhibits chemokines which reduce macrophage and neutrophil migration to inflammatory sites. Nitric oxide (NO) is a common mediator for various forms of inflammation. NO synthesis by endotoxin-stimulated macrophages and neutrophils has also shown to be inhibited by α-MSH. In addition to its effects on cytokine production, α-MSH downregulates the expression of MHC class I, CD86 and CD40 on monocytes and dendritic cells which effects antigen presentation and co-stimulation. α-MSH is also known to increase the formation of interleukin 10 (IL-10) in monocytes, which is believed to be an important component in immunosuppressive effects.
Although the molecular mechanisms of the immunomodulatory effects of α-MSH are not completely understood, a potential mechanism of action of α-MSH is its ability to inhibit nuclear factor-κB activation in cells. The inhibition of NF-κB results in a suppression of pro-inflammatory cytokine production and nitric oxide synthesis by macrophages. α-MSH functions by binding specific receptors that belong to a group of G-protein-coupled receptors with seven transmembrane domains. These receptors include the melanocortin 1 and melanocortin 3 receptors (MCR-1 and MCR-3) on macrophages by which the binding of α-MSH inhibits NF-κB. Many of the immunomodulatory effects of α-MSH are also mediated through the accumulation of cAMP. The binding of α-MSH to melanocortin receptors increases cAMP levels which may suppress the degradation of IκB and therefore inhibit NF-κB translocation and nitric oxide production.
MC1 receptors, to which α-MSH bind and stimulates has been implicated in various anti-inflammatory and immunomodulatory responses. Five types of melanocortin receptors have been identified, MC1-MC5. MC1-receptors have been found present on melanocytes, melanoma cells, macrophages, neutrophils, glioma cells, astrocytes, monocytes, endothelial cells, in certain areas of the brain, testis and ovary. There remains continued interest in compounds and methods to stimulate MC1-receptors and to produce effective anti-inflammatory and immunomodulatory responses.